RESEARCH PAPER

Vitamin D Deficiency in Ambulant Children on Carbamazepine or Sodium

Valproate Monotherapy
MINI SREEDHARAN1, KALPANA DEVADATHAN1, PA MOHAMMED KUNJU1, BINDUSHA SASIDHARAN2, JAYAKUMAR
PARAMESWARAN PILLAI3, MINIKUMARI AMMA VASUMATHY AMMA3 AND SABOORABEEGUM MUTHUBEEVI3
From Departments of 1Pediatric Neurology, 2Pediatrics, and 3Biochemistry; Government Medical College, Thiruvananthapuram,
India.
Correspondence to: Dr Kalpana Devadathan, Additional Professor, Department of Pediatric Neurology, Government Medical
College, Thiruvananthapuram, Kerala, India. vijaykalpana10@gmail.com.
Received: May 17, 2017; Initial review: July 03,2017; Accepted: January 03, 2018.

Objective: To assess the effect of monotherapy with
Carbamazepine (CBZ) and Sodium valproate (VPA) on serum 25-
OH vitamin D levels in children with epilepsy compared to
controls.
Design: Cross-sectional study.
Setting: Outpatient department of a tertiary-care Pediatric
Neurology centre, and a nearby day-care centre and school.
Study period: June 2012 to May 2013
Participants: Children with epilepsy aged 2 to 13 years on
monotherapy with CBZ (n=28) or VPA (n=28) for at least 6
months; 109 age-matched controls from a nearby day-care centre
and school.
Results: The median (IQR) values of 25 (OH) vitamin D was 18.0
ng/mL (13.7-27.3), 21.35 ng/mL (16.4 -25.2) and 30.5 ng/mL
(19.1-43.7) in CBZ, VPA and control group, respectively (P=
0.008). 60.7% of patients in CBZ group and 35.7 % in VPA group
had low 25 (OH) D levels (<20 ng/mL) compared to 27.8% in
controls (P=0.001).The serum alkaline phosphatase level was
higher in children on carbamazepine therapy (P=0.001) than
controls.
Conclusion: This study identifies significant risk of vitamin D
deficiency in ambulant children with epilepsy on monotherapy with
CBZ or VPA.
Keywords: Adverse effect; Antiepileptic drugs; Hypo-
vitaminosis D.

Published online: February 09, 2018. PII:S097475591600117

B
iochemical abnormalities of bone mineral
metabolism in children receiving
antiepileptic drugs, first identified in 1979
[1], is still a poorly studied topic from this
region. In India, it is not a routine practice to supplement
calcium or vitamin D in children on antiepileptic drugs;
even in the UK, only 3% of Pediatric neurologists were
reported to be using prophylactic calcium and vitamin D
therapy for children on anticonvulsants [2]. Available
evidence indicates that vitamin D levels in the Indian
population is below the optimal levels recommended by
the US Institute of Medicine or US Endocrinology
Society [3]. Majority of previous studies included
children on polytherapy, institutionalized children or
those with cerebral palsy who were indoors most of the
time and from geographic areas with less sunshine, all of
which are independent risk factors for low vitamin D
levels. We planned this study to assess the effect of
monotherapy with two most commonly used AEDs, CBZ
and VPA, on bone mineral metabolism in ambulatory
children with epilepsy, with normal physical and mental
development.
METHODS
Kerala is a state located at the southern tip of India and
receives adequate sunshine throughout the year.
Consecutive ambulant children (aged 2-13 years) with
epilepsy and having apparently normal physical and
mental development, and attending the Pediatric
Neurology outpatient department of a tertiary referral
hospital in Kerala between June 2012 and May 2013, on
either CBZ or VPA monotherapy for at least six months,
were included in the study after taking informed consent.
The study protocol was approved by the Institutional
Research Board and ethical clearance was granted by the
Institutional Ethical Committee. Children who received
vitamin D or calcium supplementation, those on
polytherapy with antiepileptic drugs (AEDs) or any
chronic medications likely to affect bone metabolism like
vitamin A, anabolic steroids, bisphosphonates, gluco-
corticoids, thiazides, calcitonin etc. and children with
history of malabsorption, hypothyroidism, hepatic or
renal diseases were excluded from the study. Control
group included age-matched children attending a nearby

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SREEDHARAN, et al.
day-care centre and a school, who were not on any
continuous medications during the same period of study.
Demographic data including age, weight, height,
BMI, average duration of exposure to sunlight per day,
type of epilepsy, drugs used for treatment of epilepsy,
duration of epilepsy, frequency of seizures per month,
type of epilepsy, and duration of antiepileptic therapy
were collected. Serum calcium, phosphorus, alkaline
phosphatase, proteins, urea, creatinine, aspartate amino
transferase (AST), alanine amino transferase (ALT),
fasting lipid profile and 25-hydroxy vitamin D [25 (OH)
D] levels were assessed. Serum was separated by
centrifuging at room temperature and then stored at
–20º C until vitamin D analysis was performed.
25 (OH) D level was analyzed using ELISA 96T kit
(Diametra, Italy) within two weeks of sample collection.
The lowest detectable concentration of 25 OH vitamin D
is 0.3 ng/mL at 95% confidence limit. The intra assay
variability was less than 6.4% and inter-assay variability
was less than 6.95% (precision values as per the
manufacturer). Children with serum level of 25 (OH) D
level of more than 20 ng/mL (50 nmol/L) was considered
sufficient, levels between 12-20 ng/mL (30-50 nmol/L)
were considered insufficient, and below 12 ng/mL (<30
nmol/L) were considered deficient [4].
A priori power calculation based on a previous study
[5] indicated that a sample size of 30 children in each
group would provide 80% power to detect a 10%
difference in 25(OH) D concentration, using a two-tailed
t-test, while controlling type I error rate to 5%.
Statistical analysis: Comparison of quantitative data
between two groups were analyzed by independent
sample t test or Mann Whitney U test according to the
nature of the data. Comparison of quantitative data among
more than two groups were analysed by ANOVA with post
hoc analysis or Kruskal Wallis test. Association between
TABLE I DEMOGRAPHIC CHARACTERISTICS OF CHILDREN RECEIVING ANTIEPILEPTIC DRUGS AND CONTROLS
Variable CBZ (n= 28)
Age (y) 8.0 (2.9)
Male gender, n (%) 15 (53.6)
Weight (kg) 23.2 (7.37)
Height (cm) 124.3 (15.95)
BMI (Kg/ m2 ) 14.7 (2.4)
Exposure to direct sunlight (hr/wk) 2.8 (2.1)
Duration of epilepsy 23.4
Duration of AED therapy (months) 23.4 (6-86)
All values in mean (SD); AED: Antiepileptic drugs; BMI: Body mass index; CBZ: Carbamazepine; VPA: Sodium valproate.
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ANTIEPILEPTIC DRUGS AND VITAMIN D DEFICIENCY
qualitative data were analyzed by Chi-square test. A P
value of <0.05 was taken as statistically significant. Data
analysis was performed using SPSS version 22.0.
RESULTS
56 children with epilepsy (28 each receiving CBZ and
VPA monotherapy) and 109 controls were enrolled in the
study. None of the cases or controls had fractures, bone
pain, muscle pain or muscle weakness. Clinical features of
rickets were absent in both cases and controls (Table I).
Serum albumin and protein levels were in the normal
range for all the three groups.
The median values of 25 (OH) vitamin D were 18.0
ng/mL (IQR 13.7-27.3), 21.3 ng/mL (IQR 16.4 -25.2)
and 30.1 ng/mL (IQR 19.1-43.7) in the CBZ , VPA and
control group, respectively (P=0.008). Comparison
between CBZ and Controls (P=0.01) and VPA and
Controls (P=0.02) also showed significant differences
(Fig. 1). The proportion of participants with subnormal
vitamin D levels (<20 ng/mL) were significantly different
between the groups (Table II). Alkaline phosphatase
levels were significantly higher among children on CBZ
compared to controls (P=0.001) (Table III).
DISCUSSION
This hospital-based cross-sectional study found a
significantly high proportion of children receiving AEDs
to have hypovitaminosis D, as compared to controls.
The strengths of our study include the strict selection
criteria, exclusion of bed-ridden subjects and children on
polytherapy with AEDs, and a large number of healthy
control children. Lack of exposure to natural sunlight and
osteoporosis following inactivity are two well-known
contributors of osteoporosis. Some of the previous studies
included significant percentage of children with cerebral
palsy and on polytherapy [6]. Borusiak, et al. [7] found
significant hypocalcemia and low levels of vitamin D
VPA (n=28) Control (n=109) P
8.2 (2.9) 8.9 (2.2) 0.17
13 (46.4) 62 (56.9) 0.61
25.2 (10.49) 27.7 (9.9) 0.06
126.7 (18.23) 129. 7 (12.0) 0.86
15.1 (2.8) 16.2 (4.0) 0.09
2.7(1.6) 3.01(1.83) 0.61
24.9 - 0.79
24.9 (6-84) - 0.78
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SREEDHARAN, et al. ANTIEPILEPTIC DRUGS AND VITAMIN D DEFICIENCY

estimation by DEXA scan, which accurately reflects the

FIG. 1 Box and whisker plot showing vitamin D levels in children
on valproate Or carbamazepine monotherapy.
TABLE II VITAMIN D STATUS OF CASES AND CONTROLS
Drug Vitamin D (ng/mL), no (%)
<12 (n=17) 12-20 (n=40) >20 (n=108)
CBZ 5 (17.9) 12 (42.9) 11 (39.3)
VPA 4 (14.3) 6 (21.4) 18 (64.3)
Controls 8 (7.3) 22 (20.2) 79 (72.5)
P=0.02; (<12 ng/mL – Deficient, 12-20 ng/mL Insufficient, >20 ng/mL-
Sufficient) [4], CBZ: Carbamazepine; VPA: Sodium valproate.
among 128 ambulant children on multiple antiepileptic
drugs. As all the children in our study were on
monotherapy, the alteration in various parameters can be
attributed to the drug itself. The one important limitation
of our study is the cross-sectional design; a longitudinal
follow up of these children might have been a more
accurate reflection of bone health in these children. Lee,
et al. [8] longitudinally followed up children with
epilepsy on antiepileptic drugs and found that a high
proportion of children had hypovitaminosis D before the
start of treatment, and a significant decrease in levels was
noted between the initial and the follow up after 6 months
[8]. This suggested epilepsy as a risk factor for vitamin D
deficiency, which will be augmented by antiepileptic
drugs. We did not attempt the bone mineral density
bone health, because of financial constraints and the risk
of exposure to X-ray irradiation. Other parameters like
osteocalcin levels, serum parathormone levels and
calcitonin levels were also not assayed.
Fong, et al. [9] found that Indian ethnicity, immobility
and polytherapy with AEDs were significant risk factors
for low vitamin D levels in children with epilepsy. Seth,
et al. [10] found that 83% of non-ambulant children with
cerebral palsy on antiepileptic drugs were vitamin D
deficient. Other authors have also reported low vitamin D
levels in adults and children [11,12]. However, Turan, et
al. [13] noted that CBZ, VPA and phenobarbitone therapy
did not show any effect on serum vitamin D levels, as also
reported with VPA in another study [14]. Hepatic
induction of the cytochrome P450 enzyme system leading
to increased catabolism of vitamin D is the principal
mechanism reported in case of enzyme-inducing drugs
like Carbamazepine [15]. Valproate inhibits the 25-
hydroxylase activity on vitamin D in liver mitochondria
without inhibiting the components of cytochrome P450-
linked mono-oxygenase systems [16]. It is proposed that
genetic variations like polymorphisms in vitamin D
receptor (VDR) gene may predispose one to vitamin D
deficiency [17]. The significant increase in serum alkaline
phosphatase in children on carbamazepine may be
attributed to changes in bone mineral metabolism due to
its enzyme inducing property [18]. Mikati, et al. [19]
studied the effect of low dose vs high dose vitamin D in
ambulatory adults and children on antiepileptic drugs and
found that high-dose vitamin D therapy substantially
increased bone mineral density at several skeletal sites in
adults. In children, both doses resulted in comparable
increases in bone mass.
This study shows that serum 25 OH vitamin D levels
are significantly low in children on carbamazepine or
valproate monotherapy. Children on antiepileptic drugs
should have regular monitoring of Vitamin D levels, and/
or supplementation with calcium and vitamin D even in
children with normal growth and development, no
limitation of physical activity and adequate exposure to
sunshine. The impact of antiepileptic drugs on bone health
is to be addressed by all Pediatricians, as early

TABLE III CALCIUM, PHOSPHORUS AND ALKALINE PHOSPHATASE LEVELS IN THOSE RECEIVING ANTIEPILEPTIC DRUGS AND CONTROLS
Carbamazepine (n=28) Valproate (n=28) Control (n=109) P
Calcium (mg/dL) 9.6 (0.6) 10.2 (0.8) 9.6 (1.4) 0.026
Phosphorus (mg/dL) 4.8 (0.6) 5.8 (5.2) 4.5 (0.7) 0.031
Alkaline phosphatase (IU/L) 267.8 (72.3) 191.2 (52.3) 219.2 (68.4) <0.001
All values in mean (SD).

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SREEDHARAN, et al.
WHAT IS ALREADY KNOWN?
• Vitamin D deficiency is common in children with developmental delay on multiple antiepileptic drugs.
WHAT THIS STUDY ADDS?
• Vitamin D deficiency is also seen in typically developing children on monotherapy with either Carbamazepine
or Sodium valproate monotherapy.
identification of vitamin D deficiency and
supplementation of calcium and vitamin D can help
majority of children on long term anticonvulsants. 9.
Contributors: MS,KD: conceptualised the idea, design,
collection of data, analysis, preparation of manuscript, review of
literature; PAMK: supervised the study and edited the 10.
manuscript; BA: collection and analysis of data of the control
population; JP: statistical analysis and preparation of tables and
figures; MV: biochemical analysis and interpretation of data; SB:
supervised the biochemical analysis. 11.
Funding: A research grant from SAT Hospital endowment fund.
Competing interest: None stated.
12.
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